It has been demonstrated for some time that ocular surgery of the anterior and posterior segments of the eye seriously affect the integrity of the corneal endothelium. The trauma to which the endothelial cells are subjected shows up in an increase in the thickness and a more or less significant opacification of the cornea.
In view of the damage sustained, the search was undertaken for solutions that prevent the irreversible destruction of the cells of the endothelial layer.
Ocular irrigation, necessary during these surgical procedures on the ocular sphere, has progressed step by step, began the use of sterile isotonic saline solutions.
Because the use of such solutions proved likewise to have a toxic effect, for a time the use of the Lactate-Ringer solution, which had previously served for the irrigation of other tissues of the organism, was preferred. However, it rapidly became apparent that the significant variations in pH to which this solution was subject were not suited to the maintenance of corneal integrity.
In the early 60's, a solution containing the ions essential for the maintenance of the endothelial pump (Ca++, Mg++, K+, Na+) was marketed under the name B.S.S. This mixture represented a significant advance although it was subsequently determined to be the cause of corneal edemas because of its nonphysiological composition.
Indeed, only a mixture imitating perfectly the composition of the aqueous humor is capable of causing minimal damage to the cells of the endothelium.
For this reason, an improved mixture containing glucose, sodium bicarbonate and oxidized glutathione was subsequently described in U.S. Pat. Nos. 4,443,432 and 4,550,022.
This mixture offers the advantage of being closer to the composition of human aqueous humor, containing, in addition to the essential ions described above, a physiological buffer (bicarbonate), glucose, providing energy and an antioxidant (oxidized glutathione).
The superior efficacy of this solution was demonstrated in vitro, specifically on the recovery time for the transparency of the cornea on the one hand, and the intercellular junctions on the other.
However, this preparation presents several disadvantages, specifically in its daily use. Indeed, it is an extemporaneous preparation packaged in two parts. At the time of use by the surgeon, the contents of the first container containing calcium chloride, magnesium chloride, and the oxidized glutathione, are brought into contact with the contents of the second container containing the other ions, the sodium bicarbonate, and the sodium phosphate. This form, although inconvenient for the user, permits storage of the mixture in a form that prevents solution incompatibility and the precipitation of calcium carbonate. Indeed, ocular irrigation solutions must be clear, without any suspensions or particles. The two part solution thus allows for a stability limited to 6-8 hours after preparation.
It is, therefore, apparent that this preparation is difficult to make, which leads to high production costs and consequently to a high final product cost. Its use likewise involves other significant disadvantages such as the possibility of microbial contamination during the preparation of the final mixture. Users (surgeons and para-medical personnel) can likewise forget to make the mixture, which would be detrimental to the maintenance of the corneal integrity because of an inadequate pH in the first solution being mixed with the second solution.
On the other hand, the absence of lactic acid in the mixture distances it from the definition of the perfect physiological solution. Indeed, aqueous humor and the vitreous humor contain lactate ions in a significant quantity.
It has now been discovered that it was possible to mix, in a single solution, all the elements (or their structural analogues) without exception of the liquids bathing the cornea on the one hand and the retina on the other.
Indeed, by modifying the concentration of certain elements such as the phosphates, the precautions at the point of the making of the mixture, the improvement of certain stages of the manufacturing process, and the replacement of the oxidized glutathione by a structural analogue, have allowed the industrial production of a stable, efficient, and economically advantageous composition.
These modifications and improvements involve specifically:
The decrease in the phosphate concentration;
The saturation of the solution with carbon dioxide, which has the effect of avoiding the precipitation of calcium carbonate;
The use of organic counter ions of calcium (such as glucoheptonic acid, for example) instead of calcium chloride;
The replacement of the glucose, fragile to heat sterilization, with other suppliers of cellular energy, like biological acids, such as fumaric acid, succinic acid, citric acid and their pharmaceutically acceptable salts, such as in the formula (with n between 1 and 3): ##STR1## in which: R.sub.1 is a hydrogen atom or an --OH hydroxyl,
CH--R.sub.1 may be replaced with a radical C=0 PA1 R.sub.2 is a hydrogen atom or an --OH hydroxyl, the carbon-carbon link is a single or double link; PA1 the replacement of the glucose by complex sugars such as gluconic acid, glucoheptonic acid, glucono-glucoheptonic acid for example, and their salts; PA1 the mixture with the structural analogues of reduced glutathione, like, for example, gamma amino butyric acid (GABA) or its gabaergic structural analogues, as well as its pharmaceutically acceptable salts, as in the formula (with n between 1 and 5): ##STR2## in which: R.sub.1 is a hydrogen atom or an inferior straight chain alkyl group, having from 1 to 3 carbon atoms, and including, for example, methyl, ethyl and propyl radicals, and PA1 R.sub.2 is a hydrogen atom or an inferior straight chain alkyl group, having from 1 to 10 carbon atoms, or a --NH.sub.2 radical, and including, for example, methyl, ethyl and propyl radicals.
Among the typical compounds represented by formula (2) and useful as active compounds in the ocular irrigation mixtures according to the present invention, can be listed, as non exhaustive examples, the following compounds: aminocaproic acid, glycocoll, dimethylglycine, sarcosine, the association with the monoacids, like lactic acids and its pharmaceutically acceptable salts).
These modifications lead to a perfectly clear solution, which can be sterilized with dry or moist heat. These procedures of sterilization by dry or moist heat lead to a sterile and apyrogenic solution, which is one of the essential characteristics of such a composition.
In addition to these compounds useful in the efficacy of the composition, of primary concern is the addition of mineral salts such as sodium chloride, potassium chloride, magnesium chloride, sodium bicarbonate, in quantities sufficient to form an isotonic and stable aqueous solution. The purpose of these elements is to create a favorable physiological medium which imitates the composition of natural aqueous humor.
Furthermore, the new composition allows the achievement of a solution whose extreme pH values do not vary within the limits of 6.8 and 7.6. The osmolarity of these solutions is between 290 and 310 mOsm.
All of these characteristics allow the insurance of the formulation of the composition as close as possible to physiological aqueous humor.
The pre-clinical and clinical results appearing below show the superiority of the product of the invention over the reference products, like the BSS solution, for example, or the Lactate-Ringer solution.
The compounds described in this invention were recognized as playing a role in the protection and the preservation of the cornea during surgical procedures in the ocular sphere. These compounds, associated with a compound that provides energy to the cells like glucoheptonic acid, for example, or lactic acid, and with mineral ions have shown a remarkable deturgescent effect on the corneal endothelium.